Kinase signaling pathways as targets for intervention in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related mortality in the United States. The prognosis of patients with PDAC is extremely poor with a median survival of 6 months, in part due to the advanced stage at the time of diagnosis and early metastatic spread. A considerable body of evidence points to the involvement of the tyrosine kinase and serine/threonine kinase pathways as major effectors in pancreatic cancer development and as potential targets for intervention. These pathways regulate multiple cellular processes including cell growth, proliferation, migration, invasion and resistance to apoptosis. The relatively recent introduction of novel therapies targeting tyrosine kinase and serine/threonine kinase pathways have yielded dramatic results in certain hematological malignancies, and have resulted in significant advances in our ability to treat patients with melanoma, breast, lung and colon cancer, thereby leading to improved survival and quality of life. Unfortunately, similar therapeutic improvements have not occurred in PDAC. Thus, despite encouraging phase I/II studies, the vast majority of phase-III studies have failed to demonstrate improved efficacy in PDAC. This review will provide an overview on the different kinase signaling pathways in PDAC and the supporting data on targeted therapies available from pre-clinical and clinical studies.